Lipoprotein(a) ("Lp(a)") structurally resembles low density lipoprotein ("LDU") in that both share a lipid apoprotein composition, apolipoprotein B-100 ("apo-B"), the ligand by which LDL binds to LDL receptors present on the interior surfaces of arterial walls. (Berg, Blumberg) The unique feature of Lp(a) is an additional glycoprotein, designated apoprotein(a) ("apo(a)"), which is linked to apo-B by disulfide group. The cDNA sequence of apo(a) shows a striking homology to plasminogen, with multiple repeats of kringle 4, one kringle 5, and a protease domain. The isoforms of apo(a) vary in range of 300 to 800 kD and differ mainly in their genetically determined number of kringle 4 structures. (McLean) Apo(a) has no plasmin-like protease activity. (Eaton) Serine protease activity, however, has been demonstrated. (Salonen) Like plasminogen, Lp(a) has been shown to bind lysine-sepharose, immobilized fibrin and fibrinogen, and the plasminogen receptor on endothelial cells. (Gonzales-Gronow, Hajjar, Harpel, Miles) Furthermore, Lp(a) has been demonstrated to bind to other components of the arterial wall like fibrinectin and glycosaminoglycans. The nature of these bindings, however, is poorly understood.
Essentially all human blood contains Lp(a). There can, however, be a thousand-fold range in its plasma concentration between individuals. High levels of Lp(a) are associated with a high incidence of cardiovascular disease. (Armstrong, Dahlem, Miles, Zenker) The term "cardiovascular disease" is intended to refer to all pathological states leading to a narrowing and/or occlusion of blood vessels throughout the body, but particularly atherosclerosis, thrombosis and other related pathological states, especially as occurs in the arteries of the heart muscle and the brain.
For some time, conventional medical treatment of cardiovascular disease has focused on LDL, the so called "bad cholesterol," and strategies for lowering its concentration in the bloodstream. A great many studies have been published ostensibly linking cardiovascular disease with elevated levels of LDL. As a result, most therapies for the prevention and treatment of cardiovascular disease rely on drugs that reduce serum levels of LDL in the bloodstream. More recent studies have found the beneficial effects of lowering LDL levels to be somewhat equivocal. Thus, the efficacy of these drugs and therapies continues to be a source of major debate within the medical community.
There exists therefore a need for a drug therapy for preventing or treating cardiovascular disease by (i) reducing damage to blood vessel walls, thereby reducing the binding potential Lp(a) to blood vessel walls and thus diminishing the deleterious effects of high levels of Lp(a) in the bloodstream.
There further exists a need for a treatment that employs compounds that are safe to use with few if any complicating and undesired side effects.